Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses.
Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses.
复制标题
DOI：
10.1128/mbio.00342-18
复制
发表时间：
2018-03-20
期刊：
影响因子：
6.4
通讯作者：
Gale M Jr
中科院分区：
文献类型：
--
作者：
Aarreberg LD;Wilkins C;Ramos HJ;Green R;Davis MA;Chow K;Gale M Jr
干扰素β（IFN-β）、IFN刺激基因（ISG）和炎症反应的诱导对于控制病毒感染至关重要。我们最近确定了刺激炎性细胞因子白细胞介素-1 β（IL-1β）和诱导ISG的重要联系，ISG在体内充当针对新出现的黄病毒西尼罗河病毒（WNV）的宿主限制性途径。在这里，我们利用原代树突状细胞（WNV复制的已知靶标）的离体全局转录组分析来定义这种IL-1β驱动的抗病毒应答所需的基因特征。在WNV感染过程中，缺乏IL-1受体信号传导的树突状细胞表现出细胞内在防御基因的失调和病毒控制的丧失。令人惊讶的是，我们发现在野生型细胞中，在没有感染的情况下，IL-1β处理在处理后的后期驱动IFN-β和ISG的转录。这些抗病毒先天免疫基因的表达依赖于转录因子IFN调节因子3（IRF 3），似乎反映了IL-1β信号传导从早期炎症反应到晚期IFN介导的反应的一般转变。这些数据表明，炎症和抗病毒信号通过IL-1β-至-IRF 3信号传导串扰的过程整合以控制骨髓细胞中的病毒感染。利用这些细胞因子激活宿主防御程序的策略应作为针对单个病原体的新型治疗方法进行研究。西尼罗河病毒是一种新出现的蚊媒黄病毒，可导致严重疾病，神经病理学和感染者死亡。目前，没有针对西尼罗河病毒的人类疫苗或疗法。西尼罗河病毒感染的免疫控制需要炎症和抗病毒反应，尽管这种反应的每一个分支对另一个的影响尚不清楚。我们研究的意义在于确定病毒诱导的炎症反应如何调节关键的抗病毒免疫程序，以有效控制西尼罗河病毒感染。这些数据确定了免疫控制的基本机制，可以为针对西尼罗河病毒的治疗工作提供信息，对其他神经侵入性病毒具有潜在的疗效。
Induction of interferon beta (IFN-β), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We recently identified an essential linkage of stimulation of the inflammatory cytokine interleukin-1β (IL-1β) and induction of ISGs that function as host restriction pathways against the emerging flavivirus West Nile virus (WNV) in vivo. Here we utilized ex vivo global transcriptome analysis of primary dendritic cells, known targets of WNV replication, to define gene signatures required for this IL-1β-driven antiviral response. Dendritic cells that were deficient in IL-1 receptor signaling showed dysregulation of cell-intrinsic defense genes and loss of viral control during WNV infection. Surprisingly, we found that in wild-type cells, IL-1β treatment, in the absence of infection, drove the transcription of IFN-β and ISGs at late times following treatment. Expression of these antiviral innate immune genes was dependent on the transcription factor IFN regulatory factor 3 (IRF3) and appears to reflect a general shift in IL-1β signaling from an early inflammatory response to a late IFN-mediated response. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection in myeloid cells through a process of IL-1β-to-IRF3 signaling crosstalk. Strategies to exploit these cytokines in the activation of host defense programs should be investigated as novel therapeutic approaches against individual pathogens. West Nile virus is an emerging mosquito-borne flavivirus that can result in serious illness, neuropathology, and death in infected individuals. Currently, there are no vaccines or therapies for human use against West Nile virus. Immune control of West Nile virus infection requires inflammatory and antiviral responses, though the effect that each arm of this response has on the other is unclear. The significance of our research is in defining how virus-induced inflammatory responses regulate critical antiviral immune programs for effective control of West Nile virus infection. These data identify essential mechanisms of immune control that can inform therapeutic efforts against West Nile virus, with potential efficacy against other neuroinvasive viruses.